Abstract 3266: Plasminogen Activator Inhibitor-1 Reduces Cardiac Rupture and Prevents Cardiac Remodeling in PAI-1 Transgenic Mice
Introduction: Left ventricular (LV) remodeling after myocardial infarction (MI) results in LV dilation, a major cause of congestive heart failure and sudden cardiac death. Ischemic injury and the ensuing inflammatory response participate in LV remodeling, leading to cardiac rupture and LV dilation. Plasminogen activator inhibitor (PAI-1) plays a critical role in cardiac fibrosis. We have reported that deficiency of PAI-1 in vascular wall or macrophages can initiate vascular remodeling and cardiac fibrosis in (PAI-1−/−, apoE−/−) double knockout mice. However it is unclear whether PAI-1 overexpression in hearts can reduces cardiac rupture and cardiac remodeling. We assessed the hypothesis that PAI-1 overexpression in hearts reduces cardiac rupture and attenuate cardiac remodeling compared with control mice.
Methods: Two independent transgenic lines were generated with expression of human PAI-1 driven by the murine endothelin promoter. MI was induced by coronary occlusion in 12 to 14 weeks old PAI-1 transgenic (TG) and control (C57BL/6) mice. Four, seven and 28 days after MI, LV function was assessed with echocardiography, infarct size was determined histologically and accumulation of acute inflammatory cells in zones of infarction was characterized by immunocytochemistry.
Results: As compared with control mice, the cardiac rupture decreased in PAI-1 TG mice (11.7% vs. 24.2%, n=34). Mortality rate was also reduced in PAI-1 TG mice as compared with controls (23.5% vs. 39.4%). PAI-1 TG mice exhibited markedly decreased left ventricular end-diastolic diameter (4.31±0.27 mm vs. 5.15±0.68 SD) at 28 days after MI, less profound depression of global cardiac function (17% vs. 11% fractional shortening). Markedly greater extent of infarction was demonstrated histologically in control mice compared with PAI-1 TG mice associated with striking hemorrhage and intense inflammation.
Conclusions: PAI-1 overexpression in hearts reduced cardiac rupture after MI in PAI-1 TG mice as compared with control mice. Mortality rate was decreased in PAI-1 TG mice. PAI-1 expression in hearts prevented cardiac remodeling after MI in PAI-1 TG mice.